Activation of mTOR: a culprit of Alzheimer&amp;rsquo;s disease?

Cai, Zhiyou; Chen, Guanghui; He, Wenbo; Xiao, Ming; Lv, Yan

doi:10.2147/ndt.s75717

Cited by 127 publications

(105 citation statements)

References 245 publications

(322 reference statements)

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“…Consequently, mTOR-signaling inhibition is a novel therapeutic target for AD (Z. Cai et al 2015) (Tramutola, Lanzillotta, and Di Domenico 2017). There is still much work to be done in order to decipher the precise mechanisms of L-norvaline regulation of the AKT-mTOR signaling pathway, which is beyond the scope of this paper.…”

Section: Discussionmentioning

confidence: 99%

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

Polis

Srikanth

Elliott

et al. 2018

Preprint

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The urea cycle plays a role in the pathogenesis of Alzheimer's disease (AD). Arginase-I accumulation at sites of amyloid-beta deposition is associated with L-arginine deprivation and neurodegeneration. Moreover, a positive interaction between the arginase-II and mTOR-S6K1 pathways promote inflammation and oxidative stress. In this study, we treated 3xTg-AD mice exhibiting increased ribosomal protein S6 kinase beta-1 (S6K1) activity and wild-type (WT) mice with L-norvaline. The substance combines unique properties of arginase and S6K1 inhibition. The treated 3xTg-AD mice demonstrated significantly improved acquisition of spatial memory, associated with a substantial reduction of microgliosis and shift from activated to resting phenotype. Moreover, an increase of dendritic spines density and escalation of the expression rates of neuroplasticity related proteins were followed by a decline in the levels of amyloid-beta toxic oligomeric and fibrillar species in the hippocampus. Our findings associate local amyloid-beta-driven and immune-mediated response with altered L-arginine metabolism and suggest that arginase and S6K1 inhibition by L-norvaline can delay progression of AD.

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Section: Discussionmentioning

confidence: 99%

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

Polis

Srikanth

Elliott

et al. 2018

Preprint

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“…Given the role mTOR holds in memory formation and the fine balance that may be necessary for mTOR activity to promote cognitive function, it is not surprising to observe that excessive activation of mTOR also may function as a pathological mechanism for cognitive loss and the progression of AD . Down‐stream components of mTOR that include active p70S6K can co‐localize with hyper‐phosphorylated tau deposition in the brains of patients with AD, indicating that p70S6K may assist with the accumulation of hyper‐phosphorylated tau .…”

Section: Mtor and Neurodegenerative Disordersmentioning

confidence: 99%

Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders

Maiese¹

2015

Brit J Clinical Pharma

161

122

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Neurodegenerative disorders are significantly increasing in incidence as the age of the global population continues to climb with improved life expectancy. At present, more than 30 million individuals throughout the world are impacted by acute and chronic neurodegenerative disorders with limited treatment strategies. The mechanistic target of rapamycin (mTOR), also known as the mammalian target of rapamycin, is a 289 kDa serine/threonine protein kinase that offers exciting possibilities for novel treatment strategies for a host of neurodegenerative diseases that include Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, stroke and trauma. mTOR governs the programmed cell death pathways of apoptosis and autophagy that can determine neuronal stem cell development, precursor cell differentiation, cell senescence, cell survival and ultimate cell fate. Coupled to the cellular biology of mTOR are a number of considerations for the development of novel treatments involving the fine control of mTOR signalling, tumourigenesis, complexity of the apoptosis and autophagy relationship, functional outcome in the nervous system, and the intimately linked pathways of growth factors, phosphoinositide 3‐kinase (PI 3‐K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation two homologue one (Saccharomyces cerevisiae) (SIRT1) and others. Effective clinical translation of the cellular signalling mechanisms of mTOR offers provocative avenues for new drug development in the nervous system tempered only by the need to elucidate further the intricacies of the mTOR pathway.

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“…mTORC1 negatively controls the initiation of autophagy, contributing to the formation of pathological protein aggregates. Previous studies [120,121] showed that mTOR activation could downregulate Aβ clearance by inhibiting autophagy functions with the suppression of several signaling pathways including PI3K/Akt, glycogen synthase kinase 3 (GSK-3), AMP-activated protein kinase (AMPK), and insulin/insulin-like growth factor 1 (IGF-1) [122]. In addition, the activation of mTOR contributes to aberrant hyperphosphorylated tau [123].…”

Section: Role Of Rheb In Neurodegeneration In the Hippocampusmentioning

confidence: 99%

Upregulation of Neuronal Rheb(S16H) for Hippocampal Protection in the Adult Brain

Moon

Shin

Kim

2020

IJMS

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Ras homolog protein enriched in brain (Rheb) is a key activator of mammalian target of rapamycin complex 1 (mTORC1). The activation of mTORC1 by Rheb is associated with various processes such as protein synthesis, neuronal growth, differentiation, axonal regeneration, energy homeostasis, autophagy, and amino acid uptake. In addition, Rheb–mTORC1 signaling plays a crucial role in preventing the neurodegeneration of hippocampal neurons in the adult brain. Increasing evidence suggests that the constitutive activation of Rheb has beneficial effects against neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Our recent studies revealed that adeno-associated virus serotype 1 (AAV1) transduction with Rheb(S16H), a constitutively active form of Rheb, exhibits neuroprotective properties through the induction of various neurotrophic factors, promoting neurotrophic interactions between neurons and astrocytes in the hippocampus of the adult brain. This review provides compelling evidence for the therapeutic potential of AAV1–Rheb(S16H) transduction in the hippocampus of the adult brain by exploring its neuroprotective effects and mechanisms.

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Activation of mTOR: a culprit of Alzheimer’s disease?

Cited by 127 publications

References 245 publications

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders

Upregulation of Neuronal Rheb(S16H) for Hippocampal Protection in the Adult Brain

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